Cesium cation templated selective synthesis of a "cone-shaped" sugar macrotricyclic cryptand: A dual anion-cation molecular recognition of potassium tartrate.

Cesium templated Staudinger-aza-Wittig tandem reaction (S.A.W.) has been used in the synthesis of a bis-diazacrown-bis-cellobiosyl-tetra-ureido cryptand. A novel macrotricyclic compound having a "cone-shaped" configuration was selectively obtained. Additionally, first results on potential recognition properties of the cryptand are also given.

[New therapeutic approaches in 2014 in pulmonary medicine: COPD, asthma and lung fibrosis]. / Pneumotogie. BPCO, asthme et fibrose pulmonaire.

In 2014, among new therapeutic approaches in pulmonary medicine, the role of inhaled corticosteroids has to be revaluated after the publication of the WISDOM and other studies. Their prescription should no longer be systematic even for "at risk" groups of patients, as defined by the GOLD consensus, but rather be considered on an individual basis. In the field of asthma, two major studies confirm the efficacy of mepoluzimab for the treatment of severe, eosinophilic asthma. Finally, for idiopathic pulmonary fibrosis, 2014 has taught us that treatment with N-acetylcystein is of no proven benefit, while pirfenidone and nintedanib are two new drugs that may attenuate the downhill course of the disease.

Capped guanidino-α-cyclodextrin first synthesis based on intramolecular Staudinger-Aza-Wittig (SAW) reaction.

An intramolecularly promoted SAW reaction between a phosphinimide and an isocyanate intermediate led to an original bridged trisubstituted ((A,C),E)-α-cyclodextrin. The latter was in a second step converted into a new capped (ACE)-(guanidino)-α-cyclodextrin.

[Pulmonary medicine 2012: news for the general practitioner]. / Pneumologie.

This review reports on papers published in 2012 that will most likely impact on daily medical practice in four different areas of pulmonary medicine. How should treatment of asthma with inhaled corticosteroids be adjusted on the long run? Should idiopathic pulmonary fibrosis receive treatment with immunosuppressive drugs? Is a long-term treatment with azithromycine for bronchiectasis supported by evidence, apart from patients with cystic fibrosis? And finally, can treatment of obstructive sleep apnea with continuous positive pressure (CPAP) prevent the occurrence of new, systemic hypertension?

Interest of designed cyclodextrin-tools in gene delivery.

Cyclodextrins (CyDs) currently displays even today the image of a natural macrocyclic compound largely dominant in the formation of inclusion complexes with small hydrophobic molecules. During the past 10years, advances in this field allowed to achieve more and more sophisticated CyDs derivatives opening a simple access in scale-up quantities to original and better CyD-based gene delivery systems. In addition, possibility to combine covalent and supramolecular approaches offers new venues for the design of tailor-made CyD-based nanovehicles to improve their transfection ability and gene transfer in cells. In this account, we describe our recent progress in the construction of a novel CyD-based G0 (generation number) core dendrimer, scalable to CyD oligomers by a strategy using protonable guanidine tethers and whose concept can be generalized for the assembly of CyD pre-coated dendrimers. The synthetic strategy based on an original Staudinger-Aza-Wittig tandem coupling reaction. We present an outline of the different analytical strategies to characterize CyD-ODN (cyclodextrin-oligodeoxynucleotide) complexes. Among them, Capillary electrophoresis (CE) was used to perfectly characterize our CyD-siRNA and CyD-DNA complexes and shown to be a very attractive method with advantages of low sample consumption, rapid analysis speed, and high efficiency that make this technology a major tool for association constant measurement. Finally, we present the different biological methods that can be used, in vitro, to study gene delivery, and more precisely ones we have performed to evaluate the capability of our original model bis-guanidinium-tetrakis-ß-cyclodextrin dendrimeric tetrapod, to deliver efficiently DNA or siRNA in eukaryotic cells.

Eccentric stimulation reveals an involvement of FGF6 in muscle resistance to mechanical stress.

The objective of this report was to analyse a potential role for FGF6 in muscle resistance to mechanical stress. Normal or regenerating muscles of FGF6 (-/-) mice versus wild-type mice were submitted to different protocols of damaging eccentric contractions (eccentric electrostimulation and intermittent downhill exercise). Then muscular structural properties were analysed by histological and immunochemistry techniques to evaluate the post-injury muscle recovery; their muscle contractile parameters (maximal tetanic force, kinetics properties and fatigue resistance) were assessed. The absence of FGF6 causes (1) a fast-to-slow myofibre type switch in adult control and regenerating Tibialis anterior (TA) muscle; (2) muscle weakness in regenerating muscles in animals submitted to eccentric exercise protocols due to aberrant extensive necrotic zones. These observations point out a crucial and unexpected role for FGF6 in muscle integrity and muscle protection against mechanical stress.

TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy.

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.

Alternative splicing of MLH1 messenger RNA in human normal cells.

The hMLH1 protein, composed of 756 amino acids, is the human homologue of the bacterial DNA mismatch repair protein MutL, and germ line mutations of the hMLH1 gene have been identified in kindreds with hereditary nonpolyposis colorectal cancer. We have detected three alternatively spliced forms of hMLH1 mRNA in normal lymphocytes and tissues. One of the spliced forms lacks the coding region of hMLH1 from codons 227 to 295 and the two other transcripts are predicted to encode two truncated proteins retaining the 264 and 226 N-terminal amino acids of hMLH1, respectively. The biological significance of this alternative splicing remains to be established.

Identification of novel germline hMLH1 mutations including a 22 kb Alu-mediated deletion in patients with familial colorectal cancer.

We analyzed the hMLH1 gene in 17 unrelated families with putative hereditary nonpolyposis colorectal cancer. The complete hMLH1 cDNA was amplified in one step, and after a second amplification, four overlapping segments were directly sequenced. We detected, in five families that did not meet the complete Amsterdam criteria, five alterations, including a double-base change resulting in a missense mutation (Lys-618-Ala), a splicing mutation affecting the intron 4 splice acceptor site, a 2-bp deletion at codon 726, a 7-bp deletion at codon 626, and a deletion of exons 13-16. The latter alteration was shown to result from a 22-kb genomic deletion due to a homologous recombination between Alu repeats located in introns 12 and 16. The detection of five germline hMLH1 mutations in five families that only partially fulfilled the Amsterdam criteria shows that these criteria do not allow the identification of all familial colorectal cancers due to mutations of the mismatch repair genes. The numerous Alu repeats present within the hMLH1 gene and the observation of large genomic deletions suggest that (a) Alu-mediated deletions might frequently be involved in hMLH1 inactivation, and (b) reverse transcription-PCR analysis, which allows the amplification of the entire coding region of the hMLH1 gene in one step, might be the most appropriate method for the detection of hMLH1 alterations.

Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments.

Large genomic deletions within the mismatch repair MLH1 and MSH2 genes have been identified in families with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and their detection represents a technical problem. To facilitate their detection, we developed a simple semiquantitative procedure based on the multiplex PCR of short fluorescent fragments. This method allowed us to confirm in HNPCC families three known deletions of MLH1 or MSH2 and to detect in 19 HNPCC families, in which analysis of mismatch repair genes using classical methods had revealed no alteration, a deletion of exon 5 and a duplication of MSH2 involving exons 9 and 10. The presence of such duplications, the frequency of which is probably underestimated, must be considered in HNPCC families in which conventional screening methods have failed to detect mutations.

Defibrillator electrode-chest wall coupling agents: influence on transthoracic impedance and shock success.

The purpose of this study was to determine if the difference in transthoracic impedance produced by different coupling agents affects the success of shocks for defibrillation. Three different coupling agents, Harco pads (Hewlett-Packard), Littman pads (3M) and Redux paste (Hewlett-Packard), were assessed in 10 anesthetized dogs in which ventricular fibrillation was induced by electrical stimulation of the right ventricle. Defibrillation was attempted 15 seconds later, using 50, 100 and 150 joules (selected energy). Actual delivered energy, current, impedance and the percent of the shocks that achieved defibrillation were determined for the three coupling agents. Redux paste gave significantly lower impedance and higher current than the two disposable performed coupling pads tested. Despite this, there were no significant differences in shock success among the three coupling agents. Thus, in this experimental model, over a three-fold energy range, disposable coupling pads were as effective as electrode paste for defibrillation despite the slightly higher impedance of the disposable pads.

Transthoracic defibrillation: effect of sternotomy on chest impedance.

The purpose of this study was to determine the effect of sternotomy on transthoracic impedance, a major determinant of current flow and defibrillation success. Transthoracic impedance was determined by using a validated test-pulse technique that does not require actual shocks. Seventeen patients undergoing median sternotomy were studied prospectively. Transthoracic impedance was determined before operation, 3 to 5 days after operation and (in eight patients) greater than or equal to 1 month after operation. When measured using paddle electrodes placed in the standard apex-right parasternal defibrillating position, transthoracic impedance declined after sternotomy in all patients, from 77 +/- 18 to 59 +/- 17 omega (p less than 0.01); smaller declines were demonstrated by using other electrode positions. Transthoracic impedance remained below the preoperative level in the eight patients who underwent a second set of measurements at least 1 month after operation. Six normal subjects not undergoing sternotomy underwent serial transthoracic impedance measurements at least 5 days apart; mean transthoracic impedance did not change. It is concluded that transthoracic impedance declines after sternotomy. At any operator-selected energy level a higher current flow will result after sternotomy; this may facilitate postoperative defibrillation.

Regulated expression of the proteoglycan SPOCK in the neuromuscular system.

SPOCK is prevalent in developing synaptic fields of the central nervous system (Charbonnier et al., 2000. Mech. Dev. 90, 317-321). The expression of SPOCK during neuromuscular junction (NMJ) formation was compared to agrin and acetylcholine receptor (AChR) distribution. SPOCK is detected within the myogenic masses during the early steps of embryonic development, and distributed in the cytoplasm of myotubes before coclustering with AChRs. In the adult, SPOCK is present in axons and is highly expressed by Schwann cells. SPOCK altered expression pattern after nerve lesioning, or cholinergic transmission blockade, strongly indicate that its cellular distribution at the NMJ depends on innervation.

Expression of the proteoglycan SPOCK during mouse embryo development.

SPOCK is a modular proteoglycan, with homology with proteins involved in cell adhesion processes and neurogenesis. We have previously shown that SPOCK transcripts predominate in the adult mouse brain. Here, we report its expression during mouse embryonic development by in situ hybridization, and immunocytochemistry. SPOCK is actively expressed at the onset of neurogenesis during periods of neuron migration and axonal outgrowth. At a later developmental stage, its expression is particularly prevalent within developing synaptic fields. In the peripheral nervous system, SPOCK expression is also developmentally regulated particularly in dorsal root ganglion neurons.

[HIV/AIDS prevention in the school setting: practices of biology teachers in France and in the Congo]. / La prévention du sida en milieu scolaire: pratiques d'enseignants de biologie en France et au Congo.

HIV and AIDS prevention is part of the biology class curriculum in junior high and high school in both France and the Congo. The teachers must not only present the scientific knowledge but also try to incite and convince the students to adopt certain preventive behaviours in terms of their own personal conduct. This places the teachers in the domain of having a health promotion and education role. How do teachers perceive this new role? What objectives and outcome measures have they set, and what kind of educational method do they intend to use to achieve them? Based on interviews conducted in the year 2000 of 25 teachers (12 in France and 13 in Congo-Brazzaville), a profile has been defined for each teacher based on an analysis of his/her responses with regard to their role in terms of health education and more specifically in relation to AIDS prevention. A number of questions and concems emerged from this exercise, some of which were shared in common and others were clearly country-specific.

No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia.

Several studies have reported in schizophrenia a decrease of age of onset in successive family generations, and this observation is consistent with anticipation. Anticipation is known to result from expansion of CAG repeats in several neurodegenerative disorders. Longer alleles of the KCNN3 gene, which contains a highly polymorphic CAG repeat, and encodes a neuronal small conductance calcium-activated potassium channel, have recently been shown to be over-represented in sporadic cases of schizophrenia. In this report, we tested the hypothesis of an association between longer alleles of CAG repeat in the KCNN3 gene and schizophrenia in 20 families with clinical evidence for anticipation and in 151 unrelated schizophrenic cases. No significant difference in the distributions of allele frequencies was observed between familial cases of schizophrenia and controls, and between unrelated cases and controls. Furthermore, no intergenerational CAG repeat instability was detected in the 20 families. Our results do not support the involvement of the KCNN3 (hSKCa3) gene in the etiology of schizophrenia.

Expression and neural control of myogenic regulatory factor genes during regeneration of mouse soleus.

Given the importance of the myogenic regulatory factors (MRFs) for myoblast differentiation during development, the aims of this work were to clarify the spatial and temporal expression pattern of the four MRF mRNAs during soleus regeneration in mouse after cardiotoxin injury, using in situ hybridization, and to investigate the influence of innervation on the expression of each MRF during a complete degeneration/regeneration process. For this, we performed cardiotoxin injury-induced regeneration experiments on denervated soleus muscle. Myf-5, MyoD, and MRF4 mRNAs were detected in satellite cell-derived myoblasts in the first stages of muscle regeneration analyzed (2--3 days P-I). The Myf-5 transcript level dramatically decreased in young multinucleated myotubes, whereas MyoD and MRF4 transcripts were expressed persistently throughout the regeneration process. Myogenin mRNA was transiently expressed in forming myotubes. These results are discussed with regard to the potential relationships between MyoD and MRF4 in the satellite cell differentiation pathway. Muscle denervation precociously (at 8 days P-I) upregulated both the Myf-5 and the MRF4 mRNA levels, whereas the increase of both MyoD and myogenin mRNA levels was observed later, in the late stages of regeneration (30 days P-I). This significant accumulation of each differentially upregulated MRF during soleus regeneration after denervation suggests that each myogenic factor might have a distinct role in the regulatory control of muscle gene expression. This role is discussed in relation to the expression of the nerve-regulated genes, such as the nAChR subunit gene family. (J Histochem Cytochem 49:887-899, 2001)

Pediatric defibrillation: importance of paddle size in determining transthoracic impedance.

Transthoracic impedance is a major determinant of successful defibrillation or cardioversion, but no data are available concerning the range and determinants of transthoracic impedance in children. Transthoracic impedance was measured in ten ambulatory infants, 6 weeks to 9 months of age, and 37 children, 1.5 to 15 years of age, using a previously validated "test pulse" technique that measures transthoracic impedance without actually delivering a shock. We used hand-held "pediatric" (21 cm2) and "adult" (83 cm2) electrode paddles coated with either Redux paste or Redux creme. Transthoracic impedance in children was 108 +/- 24 omega (range 61 to 212 omega) using pediatric paddles. Using adult paddles lowered the transthoracic resistance by 47% to 57 +/- 11 omega (range 29 to 101 omega), P less than .05. In infants, transthoracic impedance (measured only with pediatric paddles) was 94 +/- 17 omega (range 74 to 124 omega). Using Redux paste as the coupling agent reduced transthoracic impedance by 13% (P less than .05). Transthoracic impedance was significantly but poorly related to body weight and body surface areas, but the correlations were not sufficiently high to be clinically useful. These data indicate that the larger adult electrode paddles will minimize transthoracic impedance and should be used when the child's thorax is large enough to permit electrode to chest contact over the entire paddle surface. This transition occurred at an approximate weight of 10 kg.

Factors affecting transthoracic impedance during electrical cardioversion.

Successful cardioversion is dependent on the delivery of sufficient current. Current is determined by energy and transthoracic impedance (TTI). Our purpose was to assess factors affecting TTI in humans. Twenty-eight patients undergoing elective cardioversion were monitored up to 48 hours after shock delivery. We also studied 10 normal subjects, who did not receive shocks, for comparison. TTI declined 8% in the first hour in patients who received shocks, but also 6% in the normal subjects who wore the same pads for 1 hour but received no shocks. Twenty-four hours later, TTI returned to baseline in the nonshocked subjects but remained reduced (93% of control, p less than 0.05) in the shocked patients. There was a correlation between the total energy delivered and the decline in TTI (r = 0.69). TTI was 9% lower at end-expiration than at end-inspiration (55 +/- 3 vs 50 +/- 3 ohms, mean +/- standard error of the mean, p less than 0.01, paired t test). In the normal subjects, when a nonsalt-containing coupling agent (ultrasound coupling gel) was compared with a salt-containing gel (Redux paste), TTI was 20% higher (65 +/- 5 vs 54 +/- 4 ohms, p less than 0.01) with the nonsalt-containing gel. When no coupling agent was used, TTI was markedly higher, 160 +/- 18 ohms (p less than 0.01 vs control). After 1 hour, TTI decreased 6% in the normal subjects when salt-containing gel was used, but did not change when a nonsalt gel was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Current-based transthoracic defibrillation.

This study examines in a prospective, multicenter trial the feasibility and advantage of current-based, transthoracic defibrillation. Current-based, damped, sinusoidal waveform shocks of 18, 25, 30, 35, or 40 amperes (A) were administered beginning with 25 A for polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) or 18 A for monomorphic VT; success rates were compared with those of energy-based shocks beginning at 200 J for VF/polymorphic VT and 100 J for VT. The current-based shocks were delivered from custom-modified defibrillators that determined impedance in advance of any shock using a "test-pulse" technique; the capacitor then charged to the exact energy necessary to deliver the operator-selected current against the impedance determined by the defibrillator. Three hundred sixty-two patients received > 1 shock for VF, polymorphic VT, or monomorphic VT: 569 current- based shocks and 420 energy-based shocks. Current-based shocks of 35/40 A achieved success rates of up to 74% for VF/polymorphic VT; 30 A shocks terminated 88% of monomorphic VT episodes. Energy-based shocks of 300 J terminated 72% of VF/polymorphic VT; 200-J shocks terminated 89% of monomorphic VT. We could not demonstrate a significant increase in the success rate of current-based shocks over energy-based shocks for patients with high transthoracic impedance; this may be due to inadequate sample size. Thus, current-based defibrillation is clinically feasible and effective. A larger study will be needed to test whether current-based defibrillation is superior to energy-based defibrillation.